CN102977117A

CN102977117A - Method for synthesizing 6-bromo-2, 2-dimethyl-2H-pyridino [3, 2-B] [1, 4] oxazine-3(4H)-one

Info

Publication number: CN102977117A
Application number: CN2012104840080A
Authority: CN
Inventors: 汤木林; 丁炬平; 张仁延; 余强
Original assignee: Cgenetech Suzhou China Co Ltd
Current assignee: Cgenetech Suzhou China Co Ltd
Priority date: 2012-11-26
Filing date: 2012-11-26
Publication date: 2013-03-20

Abstract

The invention discloses a method for synthesizing 6-bromo-2, 2-dimethyl-2H-pyridino [3, 2-B] [1, 4] oxazine-3(4H)-one. The method for synthesizing 6-bromo-2, 2-dimethyl-2H-pyridino [3, 2-B] [1, 4] oxazine-3(4H)-one is that 3-hydroxyl-2-nitropyridine and sodium methoxide are dissolved in methanol, liquid bromine is dripped at low temperature under the condition of controlling the temperature to react for half a hour after completing the dripping, acetic acid is then added, continuous stirring is carried out for 10 minutes so as to obtain a crude product after the concentration, the purified crude product and ethyl 2-bromo-2, 2-dimethylacetate are esterified in N, N-dimethyl formamide under the existence of alkali, and the purified intermediate is reduced through iron powder and purified to obtain white 6-bromo-2, 2-dimethyl-2H-pyridino [3, 2-B] [1, 4] oxazine-3(4H)-one.

Description

A kind of 6-bromo-2, the synthetic method of 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone

Technical field

The present invention relates to a kind of 6-bromo-2, the synthesis technique of 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone belongs to medicine, chemical technology field.

Background technology

6-bromo-2,2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone is a kind of white solid, is the important intermediate raw materials of many medicine intermediates.

Summary of the invention

The present invention with the 3-hydroxyl that is easy to get-2-nitropyridine behind bromine in the presence of the alkali 6 with 2-bromo-2, total three steps of nitroreduction intramolecular cyclization were synthesized 6-bromo-2 after 2-dimethyl acetic acid ethyl ester became ether, 2-dimethyl-2H-pyrido [3,2-B] [1,4] oxazines-3 (4H)-ketone, total recovery is about 50%.

6-bromo-2 of the present invention, 2-dimethyl-2H-pyrido [3,2-B] [1,4] synthetic method of oxazines-3 (4H)-ketone, that 3-hydroxyl-2-nitropyridine and sodium methylate are dissolved in the methyl alcohol, the control temperature drips bromine under the low temperature, add and continue to add some acetic acid after reaction half an hour, continue to stir and concentratedly after 10 minutes obtains thick product, behind the purifying with 2-bromo-2,2-dimethyl acetic acid ethyl ester in the presence of alkali at N, become ether in the dinethylformamide, the intermediate behind the purifying obtains the 6-bromo-2 of white, 2-dimethyl-2H-pyrido [3 with the iron powder reducing purifying in acetic acid, 2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone.

Above-mentioned with 3-hydroxyl-2-nitropyridine and 2-bromo-2,2-dimethyl acetic acid ethyl ester etc. are the synthetic 6-bromo-2 of main raw material, and chemical reaction and the reaction formula of 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone are as follows:

(1) 3-hydroxyl-2-nitropyridine and sodium methylate are dissolved in the methyl alcohol, with the reaction equation of bromine bromination are:

(2) 6-bromo-3-hydroxyl-2-nitropyridine and 2-bromo-2,2-dimethyl acetic acid ethyl ester become the reaction equation of ether to be in DMF:

Product behind the one-tenth ether in acetic acid by the reaction equation of iron powder reducing intramolecular cyclization is:

Figure 2012104840080100002DEST_PATH_IMAGE003

。

Embodiment

Embodiment:

3-hydroxyl-2-nitropyridine (14g, 100 mmoles) is dissolved in the methyl alcohol (300 milliliters) with sodium methylate (5.4g, 100 mmoles), and ice-water bath is cooled to 0 ^oC, be added dropwise to bromine (16 grams, 100 mmoles), add 1.5 milliliters of acetic acid in reaction under this temperature after half an hour after adding, stir under the room temperature to concentrate after 10 minutes and obtain thick product yellow solid, this solid silica gel column chromatography, with the sherwood oil of 10:1 and eluent ethyl acetate obtain a yellow solid again the normal hexane recrystallization obtain yellow 6-bromo-3-hydroxyl-2-nitropyridine crystal (20g, 80% yield).

6-bromo-3-hydroxyl obtained in the previous step-2-nitropyridine (6.8 grams, 31 mmoles), 2-bromo-2,2-dimethyl acetic acid ethyl ester (9.08g, 50 mmoles), salt of wormwood (8.5g, 62 mmoles) at N, stir under dinethylformamide (60 milliliters) room temperature and add 100 ml waters and 100 milliliters of ethyl acetate after 48 hours, layering, water is used ethyl acetate extraction again, merge after the organic phase successively water, obtain oily matter after the anhydrous magnesium sulfate drying filtering and concentrating after the saturated common salt water washing, this oily matter silica gel column chromatography, sherwood oil and eluent ethyl acetate with 3:1 obtain yellow solid (8g, yield 72%).

Midbody compound obtained in the previous step 3(12.4 g, 37.2 mmoles) and iron powder (11.3 g, 201 mmoles) are heated to 90 at acetic acid (100 milliliters) ^oC filters after stirring after 2 hours, add after mother liquor is concentrated behind the sodium bicarbonate aqueous solution with behind the ethyl acetate extraction 3 times, merge after the organic phase when being concentrated into seldom volume with filtrated stock behind the anhydrous magnesium sulfate drying after the saturated common salt water washing, filter the 6-bromo-2 that obtains white behind the cool to room temperature, 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone crystal (9g, yield 85%).

Claims

1. 6-bromo-2 of the present invention, 2-dimethyl-2H-pyrido [3,2-B] [1,4] synthetic method of oxazines-3 (4H)-ketone, that 3-hydroxyl-2-nitropyridine and sodium methylate are dissolved in the methyl alcohol, the control temperature drips bromine under the low temperature, add and continue to add some acetic acid after reaction half an hour, continue to stir and concentratedly after 10 minutes obtains thick product, behind the purifying with 2-bromo-2,2-dimethyl acetic acid ethyl ester in the presence of alkali at N, become ether in the dinethylformamide, the intermediate behind the purifying obtains the 6-bromo-2 of white, 2-dimethyl-2H-pyrido [3 with the iron powder reducing purifying in acetic acid, 2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone.

2. 6-bromo-2 as claimed in claim, the synthetic method of 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone is characterized in that: described initial feed refers to that 3-hydroxyl-2-nitropyridine is raw material.

3. above-mentioned 6-bromo-2, the synthetic method the first step of 2-dimethyl-2H-pyrido [3,2-B] [Isosorbide-5-Nitrae] oxazines-3 (4H)-ketone is synthesized 6-bromo-3-hydroxyl-2-nitropyridine, and it is characterized in that: solvent is methyl alcohol, and bromide reagent is bromine; Temperature is-15 ^oC-5 ^oC, preferred 0 ^oC.

4. above-mentioned 6-bromo-2,2-dimethyl-2H-pyrido [3,2-B] [1,4] the synthetic 2-(6-bromo-2-nitropyridine of the synthetic method second step of oxazines-3 (4H)-ketone-3-oxygen base)-the 2 Methylpropionic acid ethyl ester, it is characterized in that: solvent is N, dinethylformamide, alkali are alkaline carbonate, preferred salt of wormwood.

5. above-mentioned 6-bromo-2,2-dimethyl-2H-pyrido [3,2-B] [1,4] the synthetic 6-bromo-2 of the 3rd step of synthetic method of oxazines-3 (4H)-ketone, 2-dimethyl-2H-pyrido [3,2-B] [1,4] oxazines-3 (4H)-ketone, it is characterized by: solvent is acetic acid, and reductive agent is iron powder, and temperature is 50 ^oC-120 ^oC, preferred 90 ^oC.